FDA Approves Gleolan

June 6, 2017 - The U.S. Food and Drug Administration (FDA) has approved Gleolan [aminolevulinic acid hydrochloride (ALA HCl)] as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization Grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery. The approved recommended reconstituted oral dose of Gleolan is 20 mg/kg administered 3 hours (range 2 to 4 hours) prior to induction of anesthesia. During neurosurgery, Gleolan is used with an operating microscope adapted with a blue emitting light source and filters for excitation light of wavelength 375 to 440 nm, and observation at wavelengths of 620 to 710 nm. Due to the risk of phototoxic reactions, do not administer phototoxic drugs for 24 hours during the perioperative period. Reduce exposure to sunlight or room lights for 24 hours postoperatively.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)

Absorption: The mean absolute bioavailability of ALA HCl following the approved recommended dose of Gleolan solution was 100%. Maximum ALA plasma concentrations were reached within a median of 0.8 hour. The Tmax for PpIX occurred within a median of 4 hours.
Protein Binding: The mean protein binding of ALA was 12% at concentrations up to approximately 25% of the maximal concentration following the approved recommended dose of Gleolan.

Half-Life: The mean half-life of ALA is approximately 1 hour. The mean elimination half-life of PpIX is 3.6 hours.

Metabolism: Exogenous ALA is metabolized to PpIX, but the fraction of administered ALA that is metabolized to PpIX is unknown. The average plasma AUC of PpIX is < 6% of that of ALA.

Excretion: The mean excretion of parent ALA in urine in the 12 hours following administration of the approved recommended dose of Gleolan was 34%.

The effect of renal or hepatic impairment on the PK of ALA following Gleolan administration is unknown.

Efficacy and Safety

The efficacy of 20 mg/kg ALA HCl was evaluated in three clinical studies (Studies 1- 3) involving patients, ages 18 to 75 years old, who had a preoperative MRI compatible with malignant glioma and were undergoing surgical resection.

Both open-labelled studies, Study 1 included 33 patients with newly diagnosed glioma and Study 2 included 36 patients with recurrent glioma. Both studies compared fluorescence (positive/negative) to tumor status (true/false) using histopathology as the reference standard.

Study 3 was a randomized, multi-center study in 415 patients with a preoperative diagnosis of high-grade glioma by MRI. In patients with confirmed high-grade glioma randomized to the ALA fluorescence arm, presence of fluorescence at a biopsy level was compared to tumor status using histopathology as the reference standard. In 4 patients with low-grade glioma who received ALA HCl, 9 out of 10 fluorescent biopsies were false negative. Determined by a central blinded read of early post-surgical MRI, the percentage of patients who had “completeness” of resection was 64% in the ALA arm and 38% in the white light control arm, with the difference of 26% (95% CI: 16%, 36%).

A total of 295, 370, and 479 biopsies were obtained in Studies 1, 2, and 3, respectively. True positive biopsies (i.e., biopsies that were positive by histopathology and fluorescence) were 176, 342, and 312, respectively. False positive biopsies (i.e., biopsies that were negative by histopathology and positive by fluorescence) were 7, 12, and 7, respectively. True negative biopsies were 27, 3, and 30, respectively. False negative biopsies were 85, 13, and 130, respectively.

The safety of Gleolan is supported by 5 clinical studies which included 527 patients with glioma who received ALA HCl and 21 healthy volunteers. Adverse reactions that occurred in > 1% of patients in the week following surgery were pyrexia, hypotension, nausea, and vomiting. Adverse reactions occurring in < 1% of patients in the first 6 weeks after surgery were chills, photosensitivity reaction, solar dermatitis, hypotension, abnormal liver function test, and diarrhea. One patient experienced respiratory failure due to drug overdose.